On Trials

Researchers at Keystone provided a comprehensive roundup of ongoing AIDS vaccine trials and related activities

By Kristen Jill Kresge

Researchers at Keystone provided a comprehensive roundup of ongoing AIDS vaccine trials and related activities. Barney Graham of the Vaccine Research Center (VRC) at the US National Institutes of Health (NIH) kicked off this series of updates with a look at the many ongoing trials with the VRC's lead vaccine candidate—a DNA plasmid vaccine containing clade B gag, pol, and nef and env genes from clades A, B, and C, followed by an adenovirus serotype 5 (Ad5) vector vaccine boost carrying the same genes excluding nef. This DNA/Ad5 candidate entered Phase II testing late last year and is now in clinical trials in several countries in partnership with the HIV Vaccine Trials Network (HVTN), IAVI, and the Walter Reed Army Institute of Research (WRAIR).

IAVI and WRAIR are evaluating this prime/boost regimen in four east African countries. Two sites working with IAVI in Kigali, Rwanda and Nairobi, Kenya are now preparing to increase the number of volunteers participating in this trial, after target enrollment was quickly met (see Vaccine Briefs). WRAIR and partners recently began recruitment at its sites in Uganda and Kenya, and enrollment will begin in May at another in Tanzania, according to an update provided by Nelson Michael of WRAIR. He also reported on a trial they are conducting in Uganda involving 31 volunteers that received the VRC's DNA candidate in a previous trial and will now be boosted with Ad5 in this subsequent trial.

In Phase I trials, Graham reported that the response after the DNA prime vaccination strongly correlates with peak CD4+ and CD8+ T cells responses after the Ad5 boost. The antibody responses, measured by ELISA, were dramatically increased following the Ad5 vaccination.

But Graham faced some tough questioning from Bruce Walker on the decision to include env genes in this vaccine, which primarily induces cellular immune responses. In his work with elite controllers, individuals that are HIV infected but control the virus below detectable levels, Walker found that responses to Gag and not Env correlated with slow disease progression. And since Env is so variable, he predicted that its presence in the vaccine may distract the immune system by drawing responses to a moving target. This point was quickly countered by Richard Koup, also of the VRC, who was in the audience. Koup emphasized that debate over gene inserts is merely an indicator of advances in the AIDS vaccine field. "We should be happy we have responses at all," he said.

These immune responses may be tested soon in a preliminary efficacy trial. Preparations for a Phase IIb "test of concept" trial are underway for the VRC's DNA/Ad5 candidate. WRAIR sites in Uganda, Kenya, and Tanzania are now being readied for this larger trial, according to Michael.

Progress was also reported on other trials at the WRAIR. Enrollment is now complete in the only ongoing Phase III trial, taking place in Thailand, evaluating the efficacy of a prime-boost administration of the ALVAC canarypox vaccine and the VaxGen gp120 vaccine, the latter having already been tested in a previous efficacy trial. The final round of immunizations with this combination will occur in July, but volunteers will be followed for an additional three years.

Michael also reported on a series of clinical trials planned by WRAIR to test prime/boost regimens of various DNA constructs and the modified vaccinia Ankara (MVA) vaccine developed by WRAIR and the NIH. These trials will take place at WRAIR sites in the US, Thailand, and Africa. Data from the Phase I trial, RV 158, testing the safety and immunogenicity of WRAIR's MVA-CMDR candidate will be presented at the 2006 AIDS vaccine meeting in Amsterdam, which will take place in August/September.

This same MVA-CMDR construct is also being evaluated in clinical trials at the Karolinska Institute (KI) in Stockholm. These Phase I trials are designed to compare the safety and immunogenicity of either intramuscular or intradermal injections of a prime vaccination with a multiclade, multigene, DNA plasmid vaccine developed at the Swedish Institute for Infectious Disease Control (SMI) followed by a boost with the MVA-CMDR from WRAIR. Forty participants receive either three DNA immunizations followed by a single MVA boost or placebo.

The final volunteer will complete the vaccination schedule this May and Eric Sandström of KI says results from this trial will also be presented in Amsterdam. "We look forward to a very pleasant presentation," he said, modestly hinting at the results. "Both immunizations have been safe and well tolerated and, compared to published results on this approach, we are encouraged by the data."

Sandström and his colleagues in Tanzania, Sweden, Germany, South Africa, and the US are also starting a trial with the same vaccines in 60 volunteers in Dar es Salaam, Tanzania, once they receive final approval from the local authorities. As part of a program sponsored by the European Union, the Karolinska Institute and SMI have been assisting with the development of clinical and laboratory capacity in Dar es Salaam.

Detailed plans for another new trial were also presented by John Hural of the HVTN. Merck and the HVTN are now completing site preparations for a Phase II "test of concept" trial with Merck's Ad5 vaccine candidate in South Africa. This candidate is already being tested in a Phase IIb trial, known as the STEP study, in North America, South America, the Caribbean, and Australia (seeRenewed Promise). But the South African trial marks the first time this candidate will be evaluated in a population where the predominantly circulating clade of HIV does not match that in the vaccine. The HIV antigens in the vaccine are from clade B, while the epidemic in South Africa is mainly clade C. Immune responses induced by the vaccine will be measured by ELISPOT against both clade B and C peptides for the first 600 volunteers. The panel of clade C peptides was designed by Steve Self of the HVTN to span all possible T-cell epitopes found in >15% of HIV isolates.

The trial will enroll 3000 volunteers at 5 HVTN sites in South Africa, 40% of whom are required to have low levels of pre-existing Ad5 immunity (antibody titers <1:200). Due to the high prevalence of pre-existing immunity to Ad5, initial expectations are that 6000 people will need to be screened across the sites in order to enroll just 1200 volunteers that meet this criterion. Hural acknowledges that this will be a huge task but emphasizes that all of the South African HVTN sites are now undergoing expansion in order to handle this number of volunteers, and he said that by the time it begins, each site will be capable of processing volunteer specimens and preparing them for shipment.

Recruitment efforts for the South African trial, HVTN 503, will also focus more on women. In the STEP study only 8-900 of the 3000 total participants are women, but in this second Phase II trial, HVTN plans to enroll equal numbers of male and female volunteers. This is reflective of the high number of infections among women in South Africa. A study of almost 12,000 15-24 year olds living in South Africa in 2003 reported that HIV prevalence in women was 15.5% and only 4.8% in men of the same age group (AIDS 19, 1525, 2005). And this is not an isolated example. "I don't think there's a case from Africa where you don't see this gut-wrenching stratification by gender," said Michael.

This study is expected to start once Merck's Ad5 neutralization assay, which will be used to determine baseline eligibility for the trial, is successfully transferred to the South African sites. Merck expects that enrollment will begin before the end of the year.